Human narcolepsy is a disabling disorder of sleep and wakefulness that affects 0.1% of the general population. The singular objective of this project is to dissect the neurochemical control of normal and pathological sleep processes using a pharmacological approach and to utilize this new knowledge in the development of new treatments for human narcolepsy. Understanding narcolepsy should not only help narcoleptic patients but also provide critical information on the neurochemical mechanisms that generate normal sleep, with possible applications that extend to other areas of sleep medicine. Research is greatly facilitated by the use of an animal model of the human disorder (autosomal recessive narcolepsy) which is independently funded for an additional two years. This project is a competitive renewal of an R01 grant that has been funded for three years. In the past funding period, we have demonstrated that cataplexy, a pathological model of REM sleep atonia, is mainly controlled by two neurochemical systems, the cholinergic and the noradrenergic systems. We have also identified a number of receptor subtypes that mediate these neurochemical effects: muscarinic M2, alpha-lb adrenergic, and D2/alpha-2 receptor subtypes. In the next period of funding, we will (1) further our identification of monoaminergic and cholinergic receptor subtypes involved in the control of cataplexy and REM sleep atonia. Coadministration studies of compounds acting on monoaminergic and cholinergic systems will also be performed to examine how these systems interact synergistically. (2) Assess the role of key non-cholinergic, non-monoaminergic systems by studying the effects of intracerebroventricular infusion of candidate peptides. (3) Characterize compound effects on sleep and wakefulness in narcoleptic canines using electroencephalographic (EEG) recording techniques. One compound from each pharmacological class that modified cataplexy in our previous studies will be explored. This will include studying the effects of these compounds on sleep-wake patterns, EEG spectral analysis, and alertness using a canine version of the Multiple Sleep Latency Test. (4) Determine the site of action of pharmacologically active compounds by local pharmacological injections and studies of immediate early gene expression. (5) Use antidepressant compounds that selectively block monoamine uptake to investigate the hypothesis that the effect of current treatments of narcoleptic patients is mediated via an activation of noradrenergic systems.